This project aims to characterize virus-cell interactions leading to AIDS pathogenesis at the cellular and molecular level; to identify important virus reservoirs and sanctuaries that result in persistent virus infection; and to characterize HIV interactions with cells of the innate immune system.[unreadable] [unreadable] Identification of all cell types persistently infected by HIV is of profound importance for the understanding of AIDS pathogenesis and for the development of better treatment regimens. We have identified a subset of CD56+CD3- natural killer (NK) cells in healthy donors that express CD4 and the HIV coreceptors CCR5 and CXCR4. These cells are expanded in the peripheral blood of some HIV infected individuals and can be productively infected by both CCR5 and CXCR4-restricted molecular clones of HIV-1 in a CD4-dependent manner. Direct infection of these important innate immune cells by HIV may be relevant for the defects in innate immunity observed in AIDS patients. [unreadable] [unreadable] The role of cytokines in HIV propagation in primary cells and tissues has been studied further. HIV coreceptor regulation and intracellular mechanisms are important controls for virus propagation. Cytokine regulation of HIV coreceptor expression is cell type specific. The exact function(s) of Vpr, a 96-amino-acid virion-associated protein shown to be important for virus replication/propagation in vivo have not reached a consensus. Vpr shows multiple activities such as participation in the nuclear translocation of the HIV-1-preintegration complex, transcriptional regulation of both the HIV-1 long terminal repeat and of cellular genes, cell cycle arrest at the G2/M boundary of cell cycle, and possibly apoptosis. We have found that Vpr interacts with 14-3-3 proteins, a family regulating subcellular localization of many proteins in the cell. 14-3-3 proteins regulate the G2/M transition by inactivating Cdc25C phosphatase. Our results indicate that Vpr promotes cell cycle arrest at the G2/M phase by facilitating association of 14-3-3 and Cdc25C.